Glioblastoma multiforme (GBM) is a deadly brain tumor without effective therapy. Oncolytic herpes simplex viral vectors (OVs) provide an attractive treatment alternative based on preclinical studies however clinical trials have thus far been disappointing showing only anecdotal evidence for complete responses. We propose vector design strategies to overcome impediments to robust vector performance. Important vector limitations include (i) inadequate intra-tumoral virus growth due to the introduction of attenuating mutations (ii) reduced vector distribution due to poor initial penetration of the tumor mass and limited spread of new virions, and (iii) tumor cell migration away from the tumor margin, limiting their accessibility to infectious virus. To meet these challenges, we propose to create an innovative oHSV that retains the full complement of HSV replication functions that will ensure optimal vector replication and lytic activity. Vector safety will be ensured by vector targeting to tumor-related receptors including tumor stem cell markers and the expression of essential virus genes will be controlled by naturally occurring micro-RNAs (miRs) that are differentially expressed in normal brain and tumor cells. In addition, the vector will be armed with human matrix metalloproteases (MMPs) that impair formation of the extracellular matrix (ECM), a natural barrier to virus spread, and with an antagonist of c-Met activation, an essential function for tumor cell growth and migration. Together these transgenes are expected to enhance intra-tumoral vector spread, increase tumor access of infectious virus and impede tumor cell migration. The safety of these vectors will be evaluated in toxicology studies using immunocompetent mice, and treatment efficacy will be examined in orthotopic mouse models involving intracranial implantation of primary human glioblastoma initiating cells (GICs) that represent the four classes of stage IV GBM. The xenografts exhibit characteristics of human glioblastoma including tumor cell migration and provide a means to evaluate the utility of this next generation of oHSV as an effective tumor therapy. We anticipate that this combination of tumor targeting, robust vector replication and enhanced vector access to tumor cells will provide a powerful technology to eradicate tumors with the potential for translation to patients.